(Days 1-90- post transplant)

They include:

• Bacterial and Fungal Infections (Refer- Febrile neutropenia)
• Viral infections including CMV reactivation
• Mucositis
• Hemorrhagic cystitis
• Graft failure
• Hepatic veno-occlusive disease
• Capillary leak syndrome
• Engraftment syndrome
• Pulmonary complications:
  • Iatrogenic volume overload
  • Cardiogenic pulmonary edema
  • Idiopathic pulmonary syndrome
  • ARDS due to chemo-radiotherapy/sepsis
  • Diffuse alveolar hemorrhage
  • Infections: Bacterial (before engraftment), Viral- especially CMV/ Fungal/PCP (after engraftment)
• Neurological complications
  • Posterior reversible encephalopathy syndrome
  • Ischemic stroke
  • Toxic/ metabolic encephalopathy
  • Intracranial hemorrhage- Usually subdural hematoma
  • Infections
  • Peripheral neuropathy
• HSCT associated thrombotic micro-angiopathy
• Renal failure
• Hemolytic anemia
• Adverse drug reactions

                                      Graft Failure

Introduction

• It is lack of hematopoietic stem cell engraftment following HSCT 
• It leads to high chances of infection and bleeding due to cytopenia
• Graft rejection is inability to detect meaningful percentage of donor hematopoietic elements. 
• Poor graft function-Failure to achieve adequate blood counts following allogeneic HCT in the presence of complete donor chimerism.
• In reduced intensity conditioning, complete donor chimeras takes several months and host bone marrow cells keep producing cells. Hence in addition to routine,to define engraftment on day 28,donor T cells (CD3+)must be >5%
• Mortality in case of graft failure->50%

Etiology

• Primary (No engraftment by day 28)
  • Rejection of graft by host immunity.
  • Insufficient CD34+ Cells in the graft
  • Recipient myelofibrosis- Faulty homing of stem cells.
  • Splenomegaly-Stem cells are sequestered in spleen.
  • Use of drugs such as methotrexate, ATG, Acyclovir, ganciclovir, cotrimoxazole, mycophenolate
  • Infections such as CMV, HHV6,fungal infections 
  • GVHD
  • Higher HLA disparity/Unrelated donor
• Secondary (Counts fall after initial engraftment)
  • Residual host immunity persistent/progressive disease
  • Low donor cell yield
  • Medication side effect
  • Infections
  • GVHD
  • Secondary is generally not seen with autologous stem cell transplants
• It is prudent to store autologous stem cells from patients undergoing MUD transplantation with can be used in case of graft failure.

Treatment strategies

• Graft failure following Auto SCT
  • Autologous backup
  • Hematopoietic growth factor supports
  • Consideration for allogeneic transplant
• Graft failure following Allo SCT
  • Autologous backup 
  • Hematopoietic growth factor support 
  • Alteration in immune suppression medication 
  • Donor lymphocytes infusion 
  • CD34+ cell boost for poor graft function
  • Regrafting using same or alternate donor.
  • Safety profile of TPO analogues is not established.

Hepatic veno-occlusive disease

(Sinusoidal obstructive syndrome)

Introduction:

• It is a syndrome of tender hepatomegaly, fluid retention, weight gain and elevated serum bilirubin appearing in first 35-40 days after HSCT.
• It is commonly seen with use of high dose cyclophosphamide
• Seen in about 15% of transplants

Risk factors:

• Prior hepatic inflammatory states
• Prior hepatic fibrosis
• Extensive pre-HSCT chemotherapy
• Prior exposure to gemtuzumabozogamicin
• Prior liver irradiation
• Conditioning including TBI
• Exposure to other agents such as sirolimus and itraconazole

Grades:

• Mild- Clinically apparent, but resolves without treatment
• Moderate- Requires diuretics and pain killers for abdominal discomfort, yet resolves without treatment
• Severe- Requires specific therapies but does not resolve before day 100 or results in death.

Pathogenesis:

Hepatic metabolism of certain drugs (especially cyclophosphamide) by Cyt-p450

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Production of several toxic metabolites (Ex: Acrolein)

↓

Remain in toxic state due to deficiency of GSH activity (Decreased GSH activity is due to previous liver disease or by action of drugs such as Busulfan, BCNU or TBI)

↓

Toxic metabolites are rich in area 3 i.e. around centrilobular veins. Hence there is damage to surrounding hepatocytes and sinusoidal endothelium resulting in thrombosis at the site of endothelial damage.

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Decreased venous outflow

↓

Post sinusoidal hypertension

Criteria for diagnosis (Seattle criteria)

• Within 20 days of HSCT, minimum 2 of below criteria (after ruling out all other differential diagnosis)
  • Bilirubin- >2gm/dL
  • Hepatomegaly or pain in the right upper quadrant
  • Weight gain- >2% of basal weight

Investigations (generally these are not done)

• Hepatic venous gradient pressure- >10mm of Hg
• Hepatic Doppler- Reversal of portal flow or higher portal vein resistive pressure
• Liver biopsy
• Serum studies: There is elevated level of plasminogen activator inhibitor 1, vWF, thrombomodulin, E. Selectin, sICAM, aminopeptides of type III collagen and hyaluronic acid.

Complications:

• Thrombocytopenia which is refractory to platelet transfusion
• Pleural effusion
• Pulmonary infiltrates
• Progressive renal, cardiac or pulmonary failure
• Confusion
• Encephalopathy
• Coma

Prophylaxis (Used in high risk patients):

• Urso deoxycholic acid
• Low dose heparin

Treatment:

• Supportive treatment
  • Analgesics
  • Restriction of sodium and water intake
  • Diuretics
• Maintain intravascular volume (using albumin/plasma expanders/transfusions) for preservation of renal flow
• Ascitic fluid tapping
• Hemodialysis
• N Acetyl cysteine infusion
• Inj. Defibrotide- 6.25mg/Kg over 2 hrs- QID- for 14 days
  • Induces antifibrotic, profibrinolytic and anti-inflammatory effects
• Transvenousintrahepaticportosystemic shunt/ Surgical shunt
• Liver transplantation

Capillary leak syndrome

Pathogenesis:

Injury to capillary endothelium (By cytokines/ VEGF)

↓

Loss of intravascular fluids into the interstitial space

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Generalized edema

Risk Factors:

• Use of G-CSF
• Higher cumulative dose of chemotherapy prior to transplant
• HLA mismatched donor grafts

Clinical features: Seen usually 15 days after HSCT

• Weight gain (>3% within 24 hrs)
• Generalized edema and pleural effusion which is not responding to frusemide therapy
• Tachycardia
• Hypotension
• Renal insufficiency

Prognosis:

• It has high mortality rate

Treatment

• Withdraw any growth factors
• IVIg
• Bevacizumab (Anti VEGF)

Engraftment syndrome

(Auto aggression syndrome, Aseptic shock syndrome)

Seen exclusively after Auto-HSCT

Incidence: 5-25%

Pathogenesis

Massive release of proinflammatory cytokines (Ex:IL2, TNF alpha, INF Gamma, IL6), M-CSF, EPO and product of degranulation

↓

Systemic endothelial damage

Clinical features and Spitzer criteria for diagnosis

• Major criteria
  • Non infectious fever- No microbiological evidence of infection and not responding to antimicrobial therapy
  • Skin rash- Maculopapular exanthema involving >25% of body surface area
  • Pulmonary edema (Documented by CT/CXR), Hypoxemia
• Minor criteria
  • Weight gain- >2.5% of basal
  • Hepatic or renal dysfunction- ≥2 times the normal
  • Transient encephalopathy which is unexplained by other causes
• Diagnosis is made if
  • 3 major criteria or
  • 2 major and 1 minor criteria within 96hrs of engraftment

Treatment:

• Inj. Methylprednisolone- 1mg/Kg every 12 hrly for 3 days, with progressive tapering over 1 week. Avoid this prior to conformation of diagnosis, as this can aggravate infections.

Prognosis:

• Complete resolution is observed in 80% in 1-5 days.

HSCT associated thrombotic microangiopathy

Seen usually on day +60

Incidence:

• Auto SCT- <4%
• Allo SCT- 15%

Risk factors:

• TBI
• Calcineurin inhibitors
• Sirolimus
• Unrelated donor grafts
• Development of GVHD
• Aspergillosis, CMV, adenoviral infection

Pathogenesis

Conditioning regimens or other less known triggering factors

↓

Generalized endothelial dysfunction

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Platelet aggregation and fibrin deposition in microcirculation

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Microangiopathic haemolytic anemia

Clinical features

• MAHA- Anemia with schistocytes in PS, with elevated LDH and features of hemolysis
• Thrombocytopenia
• Renal dysfunction
• Neurological abnormalities- Cortical blindness, seizures, 
• Rarely- Hypertension, diarrhea, proteinuria

Blood and marrow transplant clinical trials network consensus criteria

• RBC fragmentation and 2 schistocytes per HPF on peripheral smear
• Concurrent increased serum LDH
• Concurrent rise in creatinine and /or neurological dysfunction without other explanation
• Negative direct and indirect Coomb’s test

Treatment:

• Stop calcineurin inhibitors immediately, by changing GVHD prophylaxis with another drug
• Plasma exchange- Poor response (Only 35% patients respond)
• Following have been found to be useful in some cases
  • Defibrotide
  • Rituximab
  • Daclizumab
  • Baciliximab

Liver dysfunction in HSCT patients

• Infections- Cholangitislenta (sepsis of liver), fungal infections, viral hepatitis
• Immune dysfunction: GVHD
• Drug toxicity- Cyclosporine A, Azoles, methotrexate, progestogens, cotrimoxazole etc
• Venous congestion- CCF, constrictive pericarditis etc
• Capillary leak syndrome
• Veno occlusive disease
• Relapse of malignancy
• Total parenteral nutrition

Renal toxicity in HSCT patients

• Drugs- Cyclosporine, Amphotericin, aminoglycoside, loop diuretics

Diffuse Pulmonary Hemorrhage

Risk factors:

• Older age
• Previous thoracic radiation
• TBI
• Myeloablative conditioning

Pathogenesis:

• Disruption of alveolar capillary basement membrane by
  • Conditioning
  • Immune mediated events
  • Return of neutrophils with marrow recovery
  • Infections

Incidence:

• Auto SCT- 1-21%
• Allo SCT- 2-17%

Clinical features:

• Shortness of breath
• Non productive cough
• Fever
• Rarely- Hemoptysis
• Hypoxemia requiring oxygen therapy

Investigations:

• Chest X ray/ CT- Focal/ diffuse, interstitial/alveolar infiltrates located in the middle and inferior lung fields
• Bronchoalveolarlavage- Bloody aspirates

Criteria for diagnosis:

• Successive aliquots of 20ml, in at least 3 segmentary bronchi, become progressively more blood stained, indicating blood in alveoli.

Prognosis:

• Overall mortality- 60% to 100%

Treatment:

• High dose methyl prednisolone- 250-500mg- IV- 6 hrly for 4-5 days and then tapering over 2-4 weeks
• Non invasive ventilation
• Recombinant Factor- VIIa
• Aminocaproic acid
• Eternacept

Idiopathic pulmonary syndrome/ Interstitialpneumonitis/ Idiopathic pneumonia syndrome/ Noncardiogenic diffuse pulmonary injury

Introduction:

• Diffuse lung infiltrate occurring after SCT for which no infectious etiology can be identified
• Occurs in 10-15% of transplant patients
• Typically occurs 30-50 days after transplant

Risk factors:

• High dose conditioning
• TBI
• GVHD
• Older recipient age
• Prior history of smoking
• Prior thoracic irradiation
• Methotrexate for GVHD prophylaxis

Pathogenesis:

• Non infectious lung injury caused by
  • Toxic effects of conditioning
  • Immunological cell mediated injury
  • Inflammatory cytokines
  • Flora derived lipopolysaccharides
  • Occult pulmonary infections

Clinical features:

• Fever
• Dyspnea
• Productive cough
• Hypoxemia

Investigations:

• Chest X ray/CT- Diffuse alveolar/ interstitial infiltrates
• CMV- To rule out CMV pneumonitis
• BAL and lung biopsy- Must be negative for bacteria, fungi and CMV

Prognosis

• 60-80% die of progressive impairment of respiratory function

Treatment

• Supportive care with ventilator support
• High dose steroids
• Etanercept

Recent advances:

Narsoplimabfor HSCT associated thrombotic microangiopathy 

HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab, an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. With a response rate was 61%, improvement in organ function occurred in 74% of patients. It was concluded that  narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

https://doi.org/10.1200/JCO.21.02389

Avatrombopag treatment for persistent thrombocytopenia after haplo HSCT

In a retrospective study involving 69 patients with persistent thrombocytopenia (PT) following haploidentical hematopoietic stem cell transplantation (haplo-HSCT), the safety and efficacy of avatrombopag treatment were evaluated. Overall response (OR) and complete response (CR) rates were 72.5% and 58.0%, respectively, with a median time to OR and CR of 11 and 29 days, respectively. Lower baseline thrombopoietin (TPO) levels were identified as a significant independent factor predicting a better response to avatrombopag. Avatrombopag was well-tolerated, and responders demonstrated improved overall survival. The study suggests that avatrombopag is a potentially safe and effective treatment for PT after haplo-HSCT, with baseline TPO levels serving as a predictive factor for treatment response.

https://doi.org/10.1038/s41409-023-02100-6

Bloodstream Infections in Patients After Hematopoietic Stem-Cell Transplantation

In a study of hematopoietic stem-cell transplantation (HSCT) recipients at the Transplantation Center of the University Hospital in Varna, Bulgaria (January 2019–December 2021), the cumulative incidence of bloodstream infections (BSIs) was 35%, with a mean onset of 8 days post-HSCT. Gram-positive bacteria were the more common causative agents (52.3%), and the 30-day mortality rate after BSI diagnosis was 23%. Fecal colonization with multidrug-resistant (MDR) bacteria and pre-transplant BSIs were identified as significant risk factors for post-HSCT BSIs. The 4-month survival rate was 86.5%, with associations found between the type of underlying disease, previous HSCT, and 4-month survival. 
https://doi.org/10.1007/s12288-023-01645-2

Subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients

A retrospective analysis of 209 allogeneic hematopoietic cell transplantation (allo-HCT) patients assessed the clinical impact of subcutaneous immunoglobulin replacement therapy (ScIgRT) post-transplantation. Patients treated with ScIgRT (Post-ScIgRT group) from April 2017 to December 2019 showed a 2-year overall survival rate of 81%, compared to 65% in the non-ScIgRT group. The cumulative incidence of non-relapse mortality at 2 years was lower in the Post-ScIgRT group (7% vs. 18%). The Post-ScIgRT group also had a lower incidence of documented infections during the observation period (21% vs. 38%). The study suggests that ScIgRT may reduce infection rates and improve prognosis after allo-HCT.

https://doi.org/10.1111/bjh.19203

Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection

In a multicentre, phase 3 trial, researchers evaluated the efficacy and safety of extending letermovir prophylaxis for cytomegalovirus (CMV) infection from 100 to 200 days post allogeneic hematopoietic stem-cell transplantation (HSCT). Participants who remained at high risk of late CMV infection were randomly assigned to receive either 200 days of letermovir or placebo after completing initial prophylaxis. The study found that extending letermovir prophylaxis significantly reduced the incidence of late clinically significant CMV infection compared to placebo. Adverse events were similar between the letermovir and placebo groups, with no drug-related deaths reported. 

https://doi.org/10.1016/S2352-3026(23)00344-7

Narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) lacks approved treatments, but this study reveals promising real-world results with narsoplimab, a MASP-2 inhibitor targeting the lectin pathway of the complement system. In a compassionate use program from 2018 to 2023, 20 patients with high-risk TA-TMA received narsoplimab, with a 65% response rate marked by transfusion independence and clinical improvement. The 100-day overall survival was 70%, reaching 100% for responders. Narsoplimab showed no additional infection risks or safety concerns, indicating it as a potentially effective, safe treatment for high-risk TA-TMA.

https://doi.org/10.1038/s41409-024-02305-3